The long term objective of these studies is to use transgenic mice to test the hypothesis that andromedins such as keratinocyte growth factor (KGF; FGF-7) and other members of the fibroblast growth factor (FGF) family can regulate the growth and metastasis of prostatic cancer in vivo. To meet these objectives, the rat probasin (PB) gene promoter will be used to target the expression of KGF, basic fibroblast growth factor (FGF-2) and FGF-receptor (FGFR) dominant-negative mutants (FGFRdnm) specifically to prostatic epithelium in transgenic mice. Dr. Greenberg, together with collaborators, has developed the rat probasin gene promoter system to direct expression of heterologous genes specifically to the prostate in transgenic mice in a hormonally- and developmentally- regulated fashion. Furthermore, in order to develop a transgenic animal prostate cancer model system, mice carrying a PB promoter - SV40 T antigen fusion transgene (PB-Tag) have recently been generated in Dr. Greenberg's laboratory. These mice develop prostatic epithelial hyperplasia by 6 months of age and specific emphasis will be placed upon the use of these established lines of mice in these studies. The rationale for these studies is based on the implication of KGF as an andromedin that can influence, via stromal-epithelial interactions, the differentiation, growth and development of the prostate gland, and that targeting KGF over expression to prostatic epithelium of transgenic mice will deregulate normal prostatic development via an autocrine stimulatory pathway that will lead to prostatic epithelial hyperplasia in these animals. In similar fashion, FGF2 will be targeted to the prostatic epithelium of transgenic mice, since it has been shown to be activated in stromal-independent malignant prostatic epithelial cells derived from Dunning tumors. When the PB-KGF and PB-FGF2 mice are crossed to the PB- Tag mice, it can be determined whether KGF or FGF2 over expression contribute to the development of adenocarcinoma of the prostate in vivo, with subsequent metastasis. Targeted expression of specific dominant- negative FGFR mutants in prostatic epithelium will be used to distinguish between the actions of FGF-1, FGF-2 and KGF on normal prostate development. In these later studies, the PB promoter will be used to target expression of FGFR1 (IIIc) and FGFR2 (IIIb) dominant-negative mutants (dnm) to the prostate epithelium in transgenic mice to abrogate the stromal-epithelial actions mediated by FGF-1/FGF-2 or FGF-1/KGF, respectively. When the PB-FGFRdnm mice are crossed to PB-Tag mice, it can be determined which of the andromedin signals, ablated singly or in combination, inhibits the development of prostatic epithelial hyperplasia. It is anticipated that these studies will also provide the basis for the rational design, development and testing of novel gene- based therapies for prostate cancer.